EP2539323B1 - Composés comme antagonistes de la bradykinine B1 - Google Patents

Composés comme antagonistes de la bradykinine B1 Download PDF

Info

Publication number
EP2539323B1
EP2539323B1 EP11705858.6A EP11705858A EP2539323B1 EP 2539323 B1 EP2539323 B1 EP 2539323B1 EP 11705858 A EP11705858 A EP 11705858A EP 2539323 B1 EP2539323 B1 EP 2539323B1
Authority
EP
European Patent Office
Prior art keywords
amino
phenyl
hydroxy
methoxy
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP11705858.6A
Other languages
German (de)
English (en)
Other versions
EP2539323B3 (fr
EP2539323A1 (fr
Inventor
Norbert Hauel
Angelo Ceci
Henri Doods
Ingo Konetzki
Juergen Mack
Henning Priepke
Annette Schuler-Metz
Rainer Walter
Dieter Wiedenmayer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2010/052232 external-priority patent/WO2010097372A1/fr
Priority to SI201130402T priority Critical patent/SI2539323T1/sl
Priority to PL11705858T priority patent/PL2539323T6/pl
Priority to EP11705858.6A priority patent/EP2539323B3/fr
Priority to HRP20150167TT priority patent/HRP20150167T4/hr
Priority to RS20140711A priority patent/RS53710B2/sr
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP2539323A1 publication Critical patent/EP2539323A1/fr
Publication of EP2539323B1 publication Critical patent/EP2539323B1/fr
Application granted granted Critical
Priority to CY20151100211T priority patent/CY1116182T1/el
Publication of EP2539323B3 publication Critical patent/EP2539323B3/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
    • C07C211/56—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the compounds of general formula I. in which n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are defined as described below, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases, which have valuable properties, their preparation, the medicaments containing the pharmacologically active compounds, their preparation and their use.
  • the present invention relates to 3-oxopyridazine compounds and their use as B1 receptor antagonists, to pharmaceutical compositions containing these compounds and to methods of using them for the prevention or treatment of acute pain, gastralgia, neuropathic pain, inflammatory and pain receptor mediated pain , Tumor pain as well as headache.
  • B1 antagonists of the structural class Aminocyclopropancarboxamide be in WO 2005/085198 , the structural class N-biphenylmethyl-aminocycloalkanecarboxamides in WO 2003/066577 , the structural class N-biarylmethyl-aminocycloalkanecarboxamides in WO 2004/019868 , the structural class sulfonyl-substituted N- (biarylmethyl) -aminocyclopropancarboxamide in WO 2005/016886 ,
  • An essential structural feature of the novel compounds is the 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid amide group, which is in tautomeric equilibrium with the 6-hydroxy-pyridazine-4-carboxylic acid amide group:
  • the new substances are characterized by the fact that they show a strong B1 receptor blocking effect and at the same time have an improved metabolic stability.
  • R 1 is the group R 2 is H or CH 3 , R 3 and R 4 together with the carbon atom to which they are attached, a C 3-6 cycloalkylene group in which a -CH 2 unit may be replaced by an oxygen atom
  • R 5 is H or CH 3
  • R 6 is H, F, Cl or methyl
  • R 7 is H, F, Cl, Br, -CN, C 1-4 -alkyl, CF 3 , CHF 2
  • R 8 H, R 9 is F, Cl, Br, C 1-4 -alkyl, -OC 1-4 -alkyl, -SC 1-4 -alkyl
  • R 10 H, R 11 is F, Cl, Br, -CN, C 1-4 alkyl, CF 3 , CHF 2
  • X is CH or N, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.
  • An embodiment 2 of the present invention consists of the compounds of general formula I in which n, R 1, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11 and X are defined as described above in embodiment 1 and R 2 H means their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.
  • Examples of very particularly preferred compounds of the above general formula I include the following: No. structure (1) (2) (3) (4) (5) (6) (7) (8th) (9) their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.
  • the compounds of the invention including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
  • C 1-4 -alkyl (including those which are part of other groups) is understood as meaning alkyl groups having 1 to 4 carbon atoms. For example, this will be named: methyl, ethyl, n- propyl, iso- propyl, n- butyl, iso -butyl, sec -butyl and tert -butyl.
  • the abbreviations Me, Et, n Pr, i -Pr, n -Bu, i-Bu, t-Bu, etc. may be used.
  • the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals.
  • propyl includes n- propyl and iso -propyl
  • butyl includes iso -butyl, sec -butyl and tert -butyl.
  • the above-mentioned terms also include those radicals in which each methylene group may be substituted with up to two and each methyl group with up to three fluorine atoms.
  • C 3-6 -cycloalkyl means cyclic alkyl groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • compounds of the general formula I can be converted, in particular for pharmaceutical applications, into their physiologically tolerated salts with inorganic or organic acids.
  • suitable inorganic acids are, for example, hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p- toluenesulfonic acid, organic acids being, for example, malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid into consideration.
  • the compounds of general formula I contain suitable carboxylic acid functions, in particular for pharmaceutical applications in their physiologically acceptable salts with inorganic or organic bases.
  • suitable inorganic bases are alkali metal or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc hydroxides or ammonium hydroxides;
  • suitable organic amines are, for example, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.
  • the compounds of the invention may exist as racemates if they possess only one chiral element, but they may also be present as pure enantiomers, i. in (R) or (S) form.
  • the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chiral element is present in the compounds of general formula I , as well as the individual optically active enantiomers which make up the racemates mentioned.
  • a compound can exist in various tautomeric forms, the illustrated compound is not limited to a tautomeric form, but includes all tautomeric forms. This applies in particular to nitrogen-containing heteroarylene:
  • the compounds of general formula I are obtained by processes known per se, for example by the following processes:
  • the coupling is preferably carried out using methods known from peptide chemistry (see eg. Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2 ) Is carried out, for example using carbodiimides, such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl- (3-dimethylamino-propyl) carbodiimide, O - (1 H -benzotriazole-1-yl) - N, N-N ', N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1 H -benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP).
  • DEC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • the reaction rate can be increased.
  • the couplings are normally carried out with equimolar proportions of the coupling components and of the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N- methylpyrrolidone (NMP) or mixtures thereof.
  • solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N- methylpyrrolidone (NMP) or mixtures thereof.
  • an auxiliary base such as diisopropylethylamine (DIPEA, Hünig base) is additionally used.
  • An alternative method of preparing compounds of general formula I is the coupling of carboxylic acids of the general formula V, wherein all the groups are as hereinbefore defined, with amines of the general formula IV, wherein all the groups are as hereinbefore defined.
  • the compounds of general formula V are either commercially available or can be prepared by literature methods.
  • a nitrile of the general formula VI to an amine of general formula III, in which the radical R 2 denotes hydrogen on the amine nitrogen, and all other radicals are as hereinbefore defined, may be under standard conditions of catalytic hydrogenolysis with a catalyst such as Raney nickel in a solvent such as ammoniacal methanol or ethanol or with a reducing agent such as lithium aluminum hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of a Lewis acid such as aluminum chloride.
  • a catalyst such as Raney nickel
  • a reducing agent such as lithium aluminum hydride or sodium borohydride in a solvent such as tetrahydrofuran
  • Lewis acid such as aluminum chloride
  • ketones are obtained, for example, from the reaction of a nitrile of the general formula VI with an alkyl Grignard reagent, which can be converted by means of reductive amination into the compounds of the general formula III .
  • the reductive amination is carried out by known methods, for example with a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or Natriumcyanoborhydrid conveniently in a solvent such as tetrahydrofuran or dichloromethane optionally with the addition of acetic acid.
  • a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or Natriumcyanoborhydrid conveniently in a solvent such as tetrahydrofuran or dichloromethane optionally with the addition of acetic acid.
  • the ketones obtained can also be converted into oximes. The subsequent reduction of the oximes then provides compounds of general formula III.
  • CHO cells expressing the cynomolgus B1 receptor are cultured in "HAM'S F-12 medium". From confluent cultures, the medium is removed, the cells are washed with PBS buffer, scraped or detached with versene and isolated by centrifugation. Subsequently, the cells are homogenized in suspension, the homogenate is centrifuged and resuspended.
  • 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid amide group contained in all the compounds of the invention and in tautomeric equilibrium with the 6-hydroxypyridazine-4-carboxylic acid amide group is present:
  • the new substances are characterized by the fact that they show a very strong B1 receptor blocking effect and at the same time have a much better metabolic stability.
  • Metabolic stability can be measured by determining the decomposition in human hepatocytes and the rate of decomposition which is expressed as a percentage of the human hepatic blood flow (% Qh).
  • a substance with a high metabolic clearance eg> 70% Qh
  • a substance with a high metabolic clearance is expected to show a shorter duration of action in the human organism than a substance that is metabolically more stable and therefore shows a lower clearance (eg ⁇ 30% Qh). Accordingly, it is of great advantage for a desired long duration of action if the active substance has a high metabolic stability (low clearance).
  • the new substances show a low clearance in human hepatocytes, as shown in the following table: Example no. K i [nM] Clearance [% Qh] (1) 3.5 1 (3) 12 7 (5) 11 22 (6) 3.2 6
  • Metabolic degradation of the test substance is determined in a hepatocyte suspension.
  • Cryopreserved primary human hepatocytes are incubated in a suitable incubation medium (eg, Dulbecco's modified eagle medium, DMEM) containing 5% human serum.
  • a suitable incubation medium eg, Dulbecco's modified eagle medium, DMEM
  • DMEM Dulbecco's modified eagle medium
  • the cells are incubated for 6 hours in an incubator with orbital shaker. At the times 0, 0.5, 1, 2, 4 and 6h 25 ⁇ L of the medium are taken. The withdrawn medium is treated with an excess of acetonitrile and centrifuged for 5 minutes. The supernatant is removed, concentrated to dryness under nitrogen and taken up in a mixture of 25% methanol and 0.1% formic acid.
  • the decrease of the concentration of the test substance in the incubation medium is determined by a coupling of liquid chromatography to electrospray mass spectrometry certainly. The linear phase of the decrease of the concentration of the test substance in the medium is used for the calculation.
  • C0 initial concentration in the incubation [ ⁇ M]
  • CD cell density of the vital cells [10e6cells / mL]
  • AUD area under the curve [ ⁇ M xh]
  • clast concentration of the last data point [ ⁇ M]
  • k slope of the regression line for the Decrease in the test substance [h-1].
  • novel compounds and their physiologically acceptable salts are useful in the treatment of diseases and disease symptoms caused, at least in part, by the stimulation of bradykinin B1 receptors, or in which antagonizing the bradykinin-1 receptor can provide symptom relief ,
  • Another object of the present invention comprises the compounds of the invention of the above-mentioned general formula I for use as a medicament.
  • the compounds are suitable for treatment
  • the substances are suitable for causal treatment in terms of slowing down or stopping the progression of chronic progressive diseases, in particular osteoarthritis, rheumatoid arthritis and spondylarthritis.
  • Another object of the present invention comprises the use of the compounds of the invention of the above-mentioned general formula I for the preparation of a medicament for a therapeutic application in the indications mentioned above.
  • the compounds of general formula I according to the invention are preferably used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
  • treatment or “therapy” is understood to mean a therapeutic treatment of patients with overt, acute or chronic indications, on the one hand the symptomatic (palliative) treatment for the alleviation of the disease symptoms and on the other hand the causal or curative treatment of the indication with the aim to terminate the pathological condition, to reduce the severity of the pathological condition or to delay the progression of the pathological condition, depending on the type or severity of the indication included.
  • Another object of the present invention is the use of a compound of general formula I for the manufacture of a medicament for the acute and prophylactic treatment of acute pain, intestinal pain, neuropathic pain, inflammatory / pain receptor-mediated pain, tumor pain, headache disorders and pain conditions of mixed cause and another of the above-mentioned diseases.
  • the use is characterized in that it involves the administration of an effective amount of a compound of general formula I or a physiologically acceptable salt thereof to a patient in need of such treatment.
  • patient is preferably understood to mean a human.
  • these substances are also useful in the veterinary treatment of pets, exotic animals and livestock.
  • the compounds of the invention For the treatment of pain, it may be advantageous to combine the compounds of the invention with invigorating substances such as caffeine or other analgesic agents. If suitable active ingredients are available for the treatment of the cause of the pain, these can be combined with the compounds according to the invention.
  • Non-steroidal anti-inflammatory drugs such as propionic acid derivatives, which may be selected from the group consisting of alminoprofen, bucloxinic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenoic acid; Acetic acid derivatives which may be selected from the group consisting of indomethacin, acemetacin, alcofenac, isoxepac, sulindac and tolmetin; Fenamic acid derivatives which may be selected from the group consisting of meclofenamic acid, mefenamic acid and tolfenamic acid; Biphenyl carboxylic acid derivatives; Oxicams, which may be selected from the group consisting of meloxicam, piroxicam and tenoxicam; Salicylic acid derivatives which may be selected from the group consisting of acet
  • Opiate receptor agonists which may be selected, for example, from the group consisting of such as morphine, darvon, tramadol and buprenorphine.
  • Cannabinoid agonists such as GW-1000.
  • Sodium channel blockers which may be selected, for example, from the group consisting of carbamazepine, mexiletine, pregabalin, tectin and ralfinamide.
  • N-type calcium channel blockers such as ziconotide.
  • Serotonergic and noradrenergic modulators which may be selected, for example, from the group consisting of duloxetine and amitriptyline.
  • Corticosteroids which may be selected, for example, from the group consisting of betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
  • Histamine H1 receptor antagonists which may be selected, for example, from the group consisting of brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine , Desloratadine, fexofenadine and levocetirizine.
  • Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from the group consisting of zafirlukast, montelukast, pranlukast and zileuton.
  • Local anesthetics which may be selected, for example, from the group consisting of ambroxol and lidocaine.
  • TRPV1 antagonists which may be selected, for example, from the group consisting of AZD-1386, JTS-653 and PHE-377.
  • Nicotine receptor agonists such as A-366833.
  • P2X3 receptor antagonists such as A-317491.
  • anti-NGF antibodies and NGF antagonists which may for example be selected from the group consisting of JNJ-42160443 and PPH 207.
  • NK1 and NK2 antagonists such as CP-728663.
  • NMDA antagonists which may for example be selected from the group consisting of CNS-5161, AZ-756 and V-3381.
  • Potassium channel modulators such as CL-888.
  • GABA modulators such as baclofen.
  • Anti-migraine therapeutics which may be selected, for example, from the group consisting of sumatriptan, zolmitriptan, naratriptan and eletriptan.
  • the compounds of the general formula I according to the invention for the treatment of one or more of the respiratory diseases mentioned above, it may be advantageous to combine the compounds of the general formula I according to the invention with other active substances for the treatment of respiratory diseases. If suitable active substances are available for the treatment of the cause of the respiratory diseases, these can be combined with the compounds according to the invention.
  • the compounds of the general formula I can also be used in combination with other pharmacologically active substances.
  • active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 receptor (CysLT1, CysLT2, CysLT3) antagonists, inhibitors of MAP kinases such as, for example, p38, ERK1 , ERK2, JNK1, JNK2, JNK3 or SAP, LTB4 receptor (BLT1, BLT2) antagonists, EGFR inhibitors, H1 receptor antagonists, antihistamines, H4 receptor antagonists, PAF antagonists and PI3 kinase inhibitors CXCR1 and / or CXCR2 Receptor antagonists and substances for cough.
  • active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 receptor (CysLT1, CysLT2,
  • compounds which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, are preferably used according to the invention as histamine H1 receptor antagonists .
  • the acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • compounds according to the invention are preferably used, for example (5-chloro-1H-indol-2-yl) - (4-methyl-1-piperazinyl) -methanone (JNJ-7777120), optionally in the form of their racemates, Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention
  • compounds which are selected from the group consisting of: saredutant, nepadutant and figopitant, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, are used as neurokinin (NK1 or NK2) antagonists .
  • saredutant nepadutant
  • figopitant optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs
  • NK1 or NK2 neurokinin
  • substances which are selected from the group consisting of hydrocodone, caramiphene, carbetipentane and dextramethorphan, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates, are preferably used as substances for coughing ,
  • CXCR1 or CXCR2 antagonists are preferably used according to the invention as compounds, for example 3 - [[3 - [(dimethylamino) carbonyl] -2-hydroxyphenyl] amino] -4 - [[(R) -1- (5- methylfuran-2-yl) propyl] amino] cyclobut-3-ene-1,2-dione (SCH-527123), optionally in the form of its racemates, enantiomers, diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates.
  • the dose required to produce an analgesic effect is advantageously 0.01 to 3 mg / kg body weight, preferably 0.1 to 1 mg / kg when given intravenously, and 0.1 to 8 mg / kg body weight, preferably 0.5 to 3 mg / kg, respectively, when given orally once to three times a day.
  • the compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, in particular for inhalation Aerosol formulations are suitable.
  • inert conventional carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / Polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, metered aerosols or suppositories are incorporated.
  • inert conventional carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water /
  • mass spectra and / or 1 H-NMR spectra are available for the compounds prepared.
  • the ratios indicated for the flow agents relate to volume units of the respective solvents.
  • the volume units given for ammonia refer to a concentrated solution of ammonia in water.
  • the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the indicated concentrations.
  • silica gel from Millipore (MATREX TM, 35 to 70 ⁇ m) or Alox E. Merck, Darmstadt, aluminum oxide 90 standardized, 63 to 200 ⁇ m, article no: 1.01097.9050) is used.
  • Method 1 Pillar: Interchim Strategy C18, 5 ⁇ M, 4.6 x 50 mm detection: 220 - 320 nm Plasticizer A: Water / 0.1% acetic acid Plasticizer B: acetonitrile Gradient: Time in min % A % B Flow rate in mL / min 0.0 95.0 5.0 3.0 0.3 95.0 5.0 3.0 2.0 2.0 98.0 3.0 2.4 2.0 98.0 3.0 2:45 95.0 5.0 3.0 2.8 95.0 5.0 3.0
  • Method 2 Pillar: Merck Cromolite Flash RP18e, 4.6 x 25 mm Plasticizer A: Water / 0.1% formic acid Plasticizer B: Acetonitrile / 0.1% formic acid Gradient: Time in min % A % B Flow rate in mL / min 0.0 90.0 10.0 1.6 2.7 10.0 90.0 1.6 3.0 10.0 90.0 1.6 03.03 90.0 10.0 1.6
  • Method 3 Pillar: YMC
  • the compounds of the general formula I can be prepared from the following intermediates A , B and C :
  • AAV 1 amide coupling
  • AAV 3 Cleavage of the tert- butyloxycarbonyl protective group
  • the resulting amine was purified by chromatography.
  • Another way to reduce the oxime to the corresponding amine is by catalytic hydrogenation.
  • the oxime was hydrogenated in methanolic ammonia solution after addition of Raney nickel at 50 ° C and a hydrogen pressure of 50 psi until fully hydrogen uptake. If necessary, the resulting amine was purified by chromatography.
  • Example 1 6-Oxo-5,6-dihydro-pyridazine-4-carboxylic acid (1 - ⁇ [5- (4-fluoro-2-trifluoromethyl-phenylamino) -pyridin-2-ylmethyl] -carbamoyl ⁇ -cyclopropyl) -amide
  • Example 7 ( S ) -6-Oxo-1,6-dihydro-pyridazine-4-carboxylic acid ⁇ 3- [4- (4-chloro-2-trifluoromethyl-phenylamino) -2-fluoro-benzylcarbamoyl] -tetrahydrofuran 3-yl ⁇ -amide
  • Active substance and mannitol are dissolved in water. After bottling is freeze-dried.
  • the solution to the ready-to-use solution is water for injections.
  • (1), (2) and (3) are mixed and granulated with an aqueous solution of (4).
  • the dried granules are admixed with (5).
  • From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 9 mm.
  • (1), (2) and (3) are mixed and granulated with an aqueous solution of (4).
  • the dried granules are admixed with (5).
  • From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 12 mm.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) under intensive mixing. This powder mixture is filled on a capsule filling machine into size 3 hard gelatine capsules.
  • 1 suppository contains:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (7)

  1. Composés de formule générale I
    Figure imgb0078
     dans laquelle
    R1 représente le groupe
    Figure imgb0079
    R2 est H ou CH3,
    R3 et R4 conjointement avec l'atome de carbone auquel ils sont liés représentent un groupe cycloalkylène en C3 à C6, dans lequel un motif -CH2- peut être remplacé par un atome d'oxygène,
    R5 est H ou CH3,
    R6 est H, F, Cl ou un groupe méthyle,
    R7 est H, F, Cl, Br, -CN, un groupe alkyle en C1 à C4, CF3, CHF2,
    R8 est H,
    R9 est F, Cl, Br, un groupe alkyle en C1 à C4, -O-alkyle en C1 à C4, -S-alkyle en C1 à C4,
    R10 est H,
    R11 est F, Cl, Br, -CN, un groupe alkyle en C1 à C4, CF3, CHF2,
    et
    X est CH ou N,
    leurs énantiomères, leurs diastéréomères, leurs mélanges et leurs sels.
  2. Composés selon la revendication 1, caractérisés en ce que
    R2 représente H,
    leurs énantiomères, leurs diastéréomères, leurs mélanges et leurs sels.
  3. Composés selon la revendication 1 ou 2, à savoir :
    Figure imgb0080
    Figure imgb0081
    Figure imgb0082
    Figure imgb0083
    Figure imgb0084
    Figure imgb0085
    Figure imgb0086
    Figure imgb0087
    Figure imgb0088
     leurs énantiomères, leurs diastéréomères, leurs mélanges et leurs sels.
  4. Sels physiologiquement acceptables des composés selon l'une des revendications 1 à 3, avec des acides ou bases inorganiques ou organiques.
  5. Composition pharmaceutique contenant un composé selon l'une des revendications 1 à 3 ou sel physiologiquement acceptable selon la revendication 4, éventuellement conjointement avec un ou plusieurs véhicules et/ou diluants inertes.
  6. Médicament contenant un composant selon l'une des revendications 1 à 4.
  7. Composé selon l'une quelconque des revendications 1 à 4, pour son utilisation dans le traitement aigu et prophylactique de l'arthrose, de la bronchopneumopathie chronique obstructive, de douleurs aiguës, de douleurs viscérales, de douleurs neuropathiques, de douleurs inflammatoires / induites par un récepteur de la douleur, des douleurs tumorales et des céphalées, de douleurs dorsales chroniques et de douleurs dans la neuropathie diabétique.
EP11705858.6A 2009-02-26 2011-02-21 Composés comme antagonistes de la bradykinine B1 Active EP2539323B3 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PL11705858T PL2539323T6 (pl) 2010-02-23 2011-02-21 Związki jako antagoniści bradykininy B1
EP11705858.6A EP2539323B3 (fr) 2010-02-23 2011-02-21 Composés comme antagonistes de la bradykinine B1
HRP20150167TT HRP20150167T4 (hr) 2009-02-26 2011-02-21 Spojevi kao antagonisti bradikinina-b1
RS20140711A RS53710B2 (sr) 2009-02-26 2011-02-21 Jedinjenja kao antagonisti b1 bradikinina
SI201130402T SI2539323T1 (sl) 2010-02-23 2011-02-21 Spojine kot antagonisti bradikinina B1
CY20151100211T CY1116182T1 (el) 2010-02-23 2015-03-02 Ενωσεις ως β1-ανταγωνιστες της βραδυκινινης

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/EP2010/052232 WO2010097372A1 (fr) 2009-02-26 2010-02-23 Composés utilisés comme antagonistes de la bradykinine b1
EP11705858.6A EP2539323B3 (fr) 2010-02-23 2011-02-21 Composés comme antagonistes de la bradykinine B1
PCT/EP2011/052512 WO2011104203A1 (fr) 2010-02-23 2011-02-21 Composés en tant qu'antagonistes de la bradykinine b1

Publications (3)

Publication Number Publication Date
EP2539323A1 EP2539323A1 (fr) 2013-01-02
EP2539323B1 true EP2539323B1 (fr) 2014-12-03
EP2539323B3 EP2539323B3 (fr) 2017-10-04

Family

ID=43981434

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11705858.6A Active EP2539323B3 (fr) 2009-02-26 2011-02-21 Composés comme antagonistes de la bradykinine B1

Country Status (22)

Country Link
EP (1) EP2539323B3 (fr)
JP (1) JP5603955B2 (fr)
KR (1) KR101843341B1 (fr)
CN (2) CN102781916B (fr)
AP (1) AP3218A (fr)
AR (1) AR080249A1 (fr)
AU (1) AU2011219885C1 (fr)
CA (1) CA2790952C (fr)
CY (1) CY1116182T1 (fr)
DK (1) DK2539323T6 (fr)
ES (1) ES2531663T7 (fr)
IL (1) IL220680A (fr)
MA (1) MA34008B1 (fr)
MX (1) MX2012009224A (fr)
NZ (1) NZ601194A (fr)
PE (1) PE20121805A1 (fr)
PL (1) PL2539323T6 (fr)
PT (1) PT2539323E (fr)
SG (1) SG183336A1 (fr)
SI (1) SI2539323T1 (fr)
TW (1) TWI499589B (fr)
WO (1) WO2011104203A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007034620A1 (de) 2007-07-25 2009-01-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue B1-Antagonisten
CA2697946C (fr) 2007-08-29 2016-06-28 Boehringer Ingelheim International Gmbh Antagonistes b1 de bradykinine
CN102781916B (zh) 2010-02-23 2014-06-25 贝林格尔.英格海姆国际有限公司 作为缓激肽b1拮抗剂的化合物
US8901127B2 (en) 2010-08-20 2014-12-02 Boehringer Ingelheim International Gmbh Pyridazin derivatives as antagonists of the bradykinin B1 receptor
US8937073B2 (en) 2010-08-20 2015-01-20 Boehringer Ingelheim International Gmbh Disubstituted tetrahydrofuranyl compounds and their use as B1-receptor antagonists
US20210361581A1 (en) * 2018-10-22 2021-11-25 Ioi Oleo Gmbh Additive for a powder material intended for compaction into shaped bodies
US20220073471A1 (en) * 2019-01-04 2022-03-10 Jiangsu Hengrui Medicine Co., Ltd. 6-oxo-1,6-dihydropyridazine derivative, preparation method therefor and medical use thereof
WO2020169042A1 (fr) * 2019-02-20 2020-08-27 江苏恒瑞医药股份有限公司 Dérivé de promédicament de 6-oxo -1,6-dihydropyridazine, son procédé de préparation et son application en médecine
WO2021198534A1 (fr) 2020-04-04 2021-10-07 Oxurion NV Inhibiteurs de la kallicréine plasmique destinés à être utilisés dans le traitement d'une maladie à coronavirus
WO2023148016A1 (fr) 2022-02-04 2023-08-10 Oxurion NV Biomarqueur pour la réponse à une thérapie par inhibiteur de la kallicréine plasmatique

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI259079B (en) * 2002-02-08 2006-08-01 Merck & Co Inc N-biphenyl(substituted methyl)aminocycloalkanecarboxamide derivatives
RU2005108667A (ru) * 2002-08-29 2005-08-27 Мерк энд Ко., Инк. (US) Производные n-биарилметиламиноциклоалканкарбоксамида
CA2534188A1 (fr) * 2003-08-07 2005-02-24 Merck & Co., Inc. N-(biarylmethyle) aminocyclopropanecarboxamides a substitution sulfonyle
US20070189865A1 (en) * 2004-03-02 2007-08-16 Bock Mark G Amino cyclopropane carboxamide derivatives as bradykinin antagonists
EA200702358A1 (ru) 2005-05-11 2008-04-28 Никомед Гмбх Комбинация ингибитора pde4 и производного тетрагидробиоптерина
HUP0600809A3 (en) * 2006-10-27 2008-09-29 Richter Gedeon Nyrt New phenylsulfamoyl-benzamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them
ME01526B (me) * 2009-02-26 2014-04-20 Boehringer Ingelheim Int Jedinjenja kao b1 antagonisti bradikinina
CN102781916B (zh) 2010-02-23 2014-06-25 贝林格尔.英格海姆国际有限公司 作为缓激肽b1拮抗剂的化合物

Also Published As

Publication number Publication date
PT2539323E (pt) 2015-02-16
NZ601194A (en) 2014-10-31
MA34008B1 (fr) 2013-02-01
PL2539323T3 (pl) 2015-05-29
IL220680A0 (en) 2012-08-30
AP3218A (en) 2015-04-30
EP2539323B3 (fr) 2017-10-04
ES2531663T7 (es) 2018-02-13
SG183336A1 (en) 2012-09-27
PE20121805A1 (es) 2013-01-23
CN103980258B (zh) 2016-09-07
CN102781916B (zh) 2014-06-25
ES2531663T3 (es) 2015-03-18
WO2011104203A1 (fr) 2011-09-01
KR20130025864A (ko) 2013-03-12
KR101843341B1 (ko) 2018-03-30
SI2539323T1 (sl) 2015-03-31
CN103980258A (zh) 2014-08-13
DK2539323T6 (en) 2018-01-02
DK2539323T3 (da) 2015-02-23
CA2790952C (fr) 2017-07-04
JP2013519710A (ja) 2013-05-30
IL220680A (en) 2015-08-31
EP2539323A1 (fr) 2013-01-02
TW201141848A (en) 2011-12-01
AR080249A1 (es) 2012-03-21
AU2011219885B2 (en) 2015-10-15
MX2012009224A (es) 2012-08-23
CY1116182T1 (el) 2017-02-08
CA2790952A1 (fr) 2011-09-01
PL2539323T6 (pl) 2018-05-30
TWI499589B (zh) 2015-09-11
HK1175171A1 (en) 2013-06-28
JP5603955B2 (ja) 2014-10-08
AP2012006330A0 (en) 2012-06-30
AU2011219885C1 (en) 2017-06-29
AU2011219885A1 (en) 2012-08-02
CN102781916A (zh) 2012-11-14

Similar Documents

Publication Publication Date Title
EP2539323B1 (fr) Composés comme antagonistes de la bradykinine B1
EP2401256B1 (fr) Composés comme antagonistes de la bradykinine B1
EP2606042B1 (fr) Composés de tétrahydrofuranyl disubstitués en tant qu'antagonistes du récepteur b1 de la bradykinine
EP2313398A1 (fr) Hétérocycles à substitution cyclohexyloxy, médicaments contenant ces composés, leur utilisation et procédé pour les préparer
WO2010097374A1 (fr) Composés servant d'antagonistes de bradykinine b1
EP2606043B1 (fr) Dérivés de pyridazine en tant qu'antagonistes du récepteur de la bradykinine b1
EP2313397B1 (fr) Hétérocycles substitués par cyclohexyloxy, médicament contenant ces liaisons, leur utilisation et leur procédé de fabrication
AU2015271888B2 (en) Compounds as bradykinin B1 antagonists
WO2010097373A1 (fr) Composés servant d'antagonistes de bradykinine b1
HK1175171B (en) Compounds as bradykinin b1 antagonists
HK1200443A1 (en) Compounds as bradykinin b1 antagonists
HK1200443B (en) Compounds as bradykinin b1 antagonists

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120924

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

17Q First examination report despatched

Effective date: 20130723

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20140521

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

INTG Intention to grant announced

Effective date: 20141013

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 699271

Country of ref document: AT

Kind code of ref document: T

Effective date: 20141215

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 502011005155

Country of ref document: DE

Effective date: 20150115

REG Reference to a national code

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20150167

Country of ref document: HR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20150209

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20150219

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2531663

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20150318

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E010273

Country of ref document: EE

Effective date: 20150302

REG Reference to a national code

Ref country code: NO

Ref legal event code: T2

Effective date: 20141203

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20150400276

Country of ref document: GR

Effective date: 20150318

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 18016

Country of ref document: SK

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20150167

Country of ref document: HR

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 502011005155

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

26N No opposition filed

Effective date: 20150904

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E024704

Country of ref document: HU

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 6

REG Reference to a national code

Ref country code: DE

Ref legal event code: R055

Ref document number: 502011005155

Country of ref document: DE

PLCP Request for limitation filed

Free format text: ORIGINAL CODE: EPIDOSNLIM1

PLCQ Request for limitation of patent found admissible

Free format text: ORIGINAL CODE: 0009231

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

LIM1 Request for limitation found admissible

Free format text: SEQUENCE NO: 1; FILED AFTER OPPOSITION PERIOD

Filing date: 20161212

Effective date: 20161213

PLCR Communication despatched that request for limitation of patent was allowed

Free format text: ORIGINAL CODE: 0009245

REG Reference to a national code

Ref country code: DE

Ref legal event code: R056

Ref document number: 502011005155

Country of ref document: DE

Ref country code: DE

Ref legal event code: R097

Ref document number: 502011005155

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141203

PLCN Payment of fee for limitation of patent

Free format text: ORIGINAL CODE: EPIDOSNRAL3

PUAM (expected) publication of b3 document

Free format text: ORIGINAL CODE: 0009410

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN LIMITED

REG Reference to a national code

Ref country code: CH

Ref legal event code: AELM

REG Reference to a national code

Ref country code: EE

Ref legal event code: LD4A

Ref document number: E010273

Country of ref document: EE

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: NO

Ref legal event code: LC4

Effective date: 20141203

REG Reference to a national code

Ref country code: SE

Ref legal event code: REB3

Effective date: 20171004

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20150167

Country of ref document: HR

Payment date: 20180206

Year of fee payment: 8

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20180216

Year of fee payment: 8

Ref country code: NL

Payment date: 20180216

Year of fee payment: 8

REG Reference to a national code

Ref country code: SK

Ref legal event code: T5

Ref document number: E 18016

Country of ref document: SK

REG Reference to a national code

Ref country code: HR

Ref legal event code: T4IZ

Ref document number: P20150167

Country of ref document: HR

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: RO

Payment date: 20180123

Year of fee payment: 8

Ref country code: CZ

Payment date: 20180216

Year of fee payment: 8

Ref country code: FI

Payment date: 20180219

Year of fee payment: 8

Ref country code: LT

Payment date: 20180122

Year of fee payment: 8

Ref country code: ES

Payment date: 20180327

Year of fee payment: 8

Ref country code: CH

Payment date: 20180216

Year of fee payment: 8

Ref country code: DK

Payment date: 20180216

Year of fee payment: 8

Ref country code: NO

Payment date: 20180226

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171004

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: HU

Payment date: 20180213

Year of fee payment: 8

Ref country code: BE

Payment date: 20180216

Year of fee payment: 8

Ref country code: MC

Payment date: 20180214

Year of fee payment: 8

Ref country code: LV

Payment date: 20180213

Year of fee payment: 8

Ref country code: PT

Payment date: 20180216

Year of fee payment: 8

Ref country code: GR

Payment date: 20180213

Year of fee payment: 8

Ref country code: SE

Payment date: 20180227

Year of fee payment: 8

Ref country code: IE

Payment date: 20180219

Year of fee payment: 8

Ref country code: SK

Payment date: 20180220

Year of fee payment: 8

Ref country code: AT

Payment date: 20180219

Year of fee payment: 8

Ref country code: SI

Payment date: 20180129

Year of fee payment: 8

Ref country code: TR

Payment date: 20180221

Year of fee payment: 8

Ref country code: RS

Payment date: 20180125

Year of fee payment: 8

Ref country code: BG

Payment date: 20180220

Year of fee payment: 8

Ref country code: EE

Payment date: 20180220

Year of fee payment: 8

Ref country code: IS

Payment date: 20180119

Year of fee payment: 8

Ref country code: IT

Payment date: 20180227

Year of fee payment: 8

Ref country code: HR

Payment date: 20180206

Year of fee payment: 8

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20170403473

Country of ref document: GR

Effective date: 20180518

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AL

Payment date: 20180216

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20180216

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20180213

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MT

Payment date: 20180122

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MK

Payment date: 20180123

Year of fee payment: 8

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20190221

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E010273

Country of ref document: EE

Effective date: 20190228

REG Reference to a national code

Ref country code: HR

Ref legal event code: PBON

Ref document number: P20150167

Country of ref document: HR

Effective date: 20190221

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20190228

Ref country code: NO

Ref legal event code: MMEP

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20190301

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 699271

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190221

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: NO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190222

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190222

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190821

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 18016

Country of ref document: SK

Effective date: 20190221

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20190228

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190831

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: RS

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190909

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190904

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190222

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20191007

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190829

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

Ref country code: HR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190301

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20200331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190221

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190221

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20260219

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20260218

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20260218

Year of fee payment: 16